1. Field of the Invention
The present invention relates to a novel method of treating psoriasis, a disease of the skin. The method comprises using vitamin D-related compounds.
2. Brief Description of the Background Art
Psoriasis is a disease of the epidermis and a major cause of disability and disfigurement, for between 2,000,000 and 8,000,000 persons in the United States. Of these, about 100,000 are severely affected.
The disease is diagnosed by the presence of scaling erythematous on the scalp and extender aspects of the arms and legs; psoriatic lesions often are accentuated on the sites of repeated trauma, such as the elbows and knees. The papules or plaques of psoriasis often contain a silvery-white micaceous scale that is relatively easily removed in layers. There is a several fold increase in the normal number of the basal cells of the epidermis. This increase in the basal cell population reduces the turnover time of the epidermis from the normal 27 days to 3-4 days. This shortened interval leads to the consequence that normal events of call maturation or keratinization do not occur, and this failure of maturation is reflected by an array of abnormal morphologic and biochemical changes. Numerous cytologic, histologic, histochemical and biochemical alterations are now known to be the result, rather than the cause of the disease process. The only main fact known at this time about the fundamental cause of psoriasis is that the predisposition to its development is genetically transmitted. (This introduction is basically taken from Harrison's Principles of Internal Medicine, 10th Ed., Vol, 1, pp. 256 and 257).
The treatment of psoriasis still remains the province of dermatologists. The most effective treatment in the control of localized psoriasis for most patients is the topical use of corticosteroids with a plastic wrap and ultraviolet light or sunlight exposures. On certain patients who have generalized psoriasis, it has been necessary to use a variety of systemic chemotherapeutic agents, especially methotrexate; the latter has the capacity to inhibit cell replication without a proportionate inhibition of cell function; i.e. keratinization. Photochemotherapy was introduced in 1974, in the so-called PUVA treatment. In this treatment, psoralen is administered two hours before total body irradiation with a special light system that emits predominantly long wave ultraviolet light. The light alone is ineffective in producing erythema or remission of psoriatic lesions; however, in the presence of one of the psoralens, the UV-A light becomes a potent photoactive agent and produces a remission of psoriatic lesions after several exposures. Photochemotherapy requires specialized knowledge and lighting systems delivering precisely measured amounts of ultraviolet light.
Along quite different areas of research, Holick et al. (New England Journal of Medicine, 303: 349-354 (1980)) have studied the feasibility of using the skin as the organ for the synthesis and absorption of vitamin D metabolites. These investigators demonstrated that topical application of various vitamin D metabolites or pro-vitamin forms followed by phototherapy results in elevated serum levels of dihydroxy-vitamin D.sub.3. It was therefore suggested that topical application of vitamin D analogues may be an effective method of therapy for diseases involving calcium, phosphorus and bone metabolism problems. It is only recently, however, that it has become clear that the skin itself may be a target tissue for 1,25--(OH).sub.2 --D.sub.3 (Stumpf, W. E. et al., Science, 206:1188-1190 (1979)). Cells isolated from the skin of rats, mice, and humans, and from cultured human skin fibroblasts and keratinocytes contain a high affinity (1.0.times.10.sup.-10 M) low capacity receptor-like protein for 1,25-dihydroxy-vitamin D.sub.3 (Franceschi, et al., Arch. Biochem. Biophys, 210: 1-13 (1979); Simpson, R. U. et al., P.N.A.S. USA, 77: 5822 (1980); Colston, K. et al., Endocrinology, 107: 1916 (1980); Feldman D. et al., Journal of Clinical Endocrinology & Metabolism, 51: 1463 (1980); Eil, C. et al., P.N.A.S. USA, 78: 2562 (1981); and Clemens, T. L. et al., J. Clin. Endocr. Metab. 56: Apr. 1983). A specific biological function for 1,25-(OH).sub.2 -vitamin D.sub.3 in the skin, however, has yet to be discovered. Nevertheless, evidence has come forth supporting the concept that the dihydroxy metabolite of the vitamin does have biologic actions in the skin. This was accomplished by evaluating the biological activity of 1,25-dihydroxy-D.sub.3 simultaneously in cultured human skin fibroblasts that either possessed or lacked a cytosolic receptor-like protein for the hormone (Clements, T. L. et al., J. Clin. Endocrinol. Metab., 56: Apr. 1983). The receptor-negative skin fibroblasts were obtained from a patient with a rare bone disorder called vitamin D dependent rickets, type ii, a heritable disorder caused by a defective or complete absence of a cytoplasmic or nuclear receptor for 1,25-dihydroxy vitamin D. The dihydroxy metabolite of vitamin D.sub.3 caused a dose-dependent inhibition of cell growth in receptor positive skin fibroblasts (about 40-50% reduction in cell growth was observed in cultures containing 10.sup.-6 and 10.sup.-8 M of hormone and 12% in cultures containing 10.sup.-10 M of 1,25--(OH).sub.2 --D.sub.3), and, by contrast, had absolutely no effect on the growth of receptor negative skin fibroblasts.
The aforementioned seemingly two divergent lines of research, the treatment of psoriasis on the one hand, and the effects of vitamin D.sub.3 on skin components on the other, remained heretofore unrelated until, by the present invention, they have been brought together.